Exploring the Mechanism of Dangguiliuhuang Decoction Against Hepatic Fibrosis by Network Pharmacology and Experimental Validation.
Exploring the Mechanism of Dangguiliuhuang Decoction Against Hepatic Fibrosis by Network Pharmacology and Experimental Validation.
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网络药理学及实验验证探讨当归六黄汤抗肝纤维化作用机制
DOI：
10.3389/fphar.2018.00187
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发表时间：
2018
影响因子：
5.6
通讯作者：
Xiang M
中科院分区：
文献类型：
--
作者：
Cao H;Li S;Xie R;Xu N;Qian Y;Chen H;Hu Q;Quan Y;Yu Z;Liu J;Xiang M
当归六黄汤（DGLHD）已被证明可有效治疗炎症、肝脂肪变性和胰岛素抵抗。在本研究中，我们试图通过网络分析和实验验证阐明DGLHD抗肝纤维化的药理功效和机制，并预测潜在的活性成分和靶点。配方中，我们共发现黄芩素、小檗碱、汉黄芩素等76种潜在活性成分，以及PTGS（前列腺素内过氧化物合酶）2、PPAR（过氧化物酶体增殖物激活受体）-γ、NF-κB（核因子-κB）等286个相应靶点。这些假定靶标的通路和功能富集分析表明，DGLHD 明显影响 NF-κB 和 PPAR 信号通路。一致地，DGLHD 下调 ALT（丙氨酸转氨酶）和 AST（天冬氨酸转氨酶）水平，减少肝纤维化小鼠血清和肝脏中促炎细胞因子 TNF（肿瘤坏死因子）-α 和 IL（白细胞介素）-1β 的产生，并抑制肝星状细胞 (HSC)-T6 细胞增殖。 DGLHD 还降低 TGF（转化生长因子）-β1 和 α-SMA（平滑肌肌动蛋白）表达，维持 MMP（基质金属蛋白）13-TIMP（金属蛋白酶组织抑制剂）1 平衡，从而减轻体内和体外 ECM（细胞外基质）沉积。此外，我们的实验数据证实，炎症减轻和 ECM 积累与 NF-κB 抑制和 PPAR-γ 激活有关。总体而言，我们的结果表明，DGLHD旨在通过改善异常炎症和ECM沉积来多靶点并阻止肝纤维化的进展，从而成为临床治疗肝纤维化的新方案。
Dangguiliuhuang decoction (DGLHD) has been demonstrated to be effective in treating inflammatory, hepatic steatosis, and insulin resistance. In the study, we tried to elucidate the pharmacological efficacy and mechanism of DGLHD against liver fibrosis and predicate potential active ingredients and targets via network analysis and experimental validation. In the formula, we totally discovered 76 potential active ingredients like baicalein, berberine, and wogonin, and 286 corresponding targets including PTGS (prostaglandin-endoperoxide synthase) 2, PPAR (peroxisome proliferator-activated receptors) -γ, and NF-κB (nuclear factor-κB). Pathway and functional enrichment analysis of these putative targets indicated that DGLHD obviously influenced NF-κB and PPAR signaling pathway. Consistently, DGLHD downregulated levels of ALT (alanine transaminase) and AST (aspartate transaminase), reduced production of proinflammatory cytokines-TNF (tumor necrosis factor) -α and IL (Interleukin) -1β in serum and liver from mice with hepatic fibrosis, and inhibited hepatic stellate cell (HSC)-T6 cells proliferation. DGLHD decreased TGF (transforming growth factor) -β1 and α-SMA (smooth muscle actin) expression as well, maintained MMP (matrix metalloprotein) 13-TIMP (tissue inhibitor of metalloproteinases) 1 balance, leading to mitigated ECM (extracellular matrix) deposition in vivo and in vitro. Moreover, our experimental data confirmed that the alleviated inflammation and ECM accumulation were pertinent to NF-κB inhibition and PPAR-γ activation. Overall, our results suggest that DGLHD aims at multiply targets and impedes the progression of hepatic fibrosis by ameliorating abnormal inflammation and ECM deposition, thereby serving as a novel regimen for treating hepatic fibrosis in clinic.
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